13-32316463-G-T

Variant names:

• chr13-32316463-G-T
• rs80358650
• NM_000059.4:c.3G>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.3G>T​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.44
• Publications: 31 publications found

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 199 pathogenic variants. Next in-frame start position is after 124 codons. Genomic position: 32325129. Lost 0.036 part of the original CDS.
• PS1: Another start lost variant in NM_000059.4 (BRCA2) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32316463-G-T is Pathogenic according to our data. Variant chr13-32316463-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.3G>T	p.Met1?	start_lost	Exon 2 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.3G>T	p.Met1?	start_lost	Exon 2 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.3G>T	p.Met1?	start_lost	Exon 2 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.3G>T	p.Met1?	start_lost	Exon 2 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.3G>T	p.Met1?	start_lost	Exon 2 of 27	ENSP00000439902.1
	BRCA2	ENST00000614259.2	TSL:2	n.3G>T		non_coding_transcript_exon	Exon 1 of 26	ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 25, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Pathogenic:2

Mar 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the disruption of the N-terminal part of the BRCA2 protein that interacts with PALB2 (residues 18-40), which is critical for BRCA2-mediated homologous recombinational DNA repair (PMID: 16793542, 22678057, 19369211). For these reasons, this variant has been classified as Pathogenic. A different variant (c.3G>A) affecting the same codon observed here (initiator codon) has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21203900, 21769658, 20104584), indicating that this residue may be critical for protein function. This variant has been reported in individuals affected with breast cancer (PMID: 26287763). ClinVar contains an entry for this variant (Variation ID: 37871). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the BRCA2 mRNA. The next in-frame methionine is located at codon 124, which could potentially rescue translational initiation.

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Breast and/or ovarian cancer Pathogenic:1

Dec 13, 2005

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 06, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.3G>T) is located in coding exon 1 of the BRCA2 gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-1.1	T
PhyloP100		5.4
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.92
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0193)
MVP		0.94
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.042	Neutral
gMVP		0.51
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80358650; hg19: chr13-32890600;